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Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection

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ABSTRACT

The controlled induction of haemoxygenase‐1 (HO‐1), an enzyme that catabolizes haem, has been shown to reduce haem, preventing pathologies associated with haem toxicity. The hemoglobin genotype HbAS confers reduced susceptibility to severe complications of malaria by a mechanism that is not well understood. Using a longitudinal approach, we investigated the effect of baseline concentrations of HO‐1 on the accumulation of haem during acute Plasmodium falciparum malaria in HbAS and HbAA genotypes. Plasma concentrations of haem, HO‐1 and cytokines were quantified in venous blood obtained from children (9 months–5 years of age) during malaria infection, and at convalescence (baseline levels). Parasitaemia was determined during malaria infection. In patients with the HbAA genotype, there was a significant elevation in the plasma concentration of haem (P = 0.002), and a consequent increased induction of HO‐1 (P < 0.001) during falciparum malaria compared with levels at convalescence. Contrary to HbAA, plasma concentration of haem did not change in the HbAS genotypical group (P = 0·110), and the induction of HO‐1 was reduced during malaria compared with levels at convalescence (P = 0·006). Higher plasma levels of haem were observed in HbAS compared with HbAA at convalescence (P = 0·010), but this difference did not affect the levels of HO‐1 within each genotype (P = 0·450). Relatively milder proinflammatory responses were observed in HbAS children during malaria infection compared to HbAA children. Our findings suggest that a mechanism of reduced susceptibility to severe malaria pathologies by the HbAS genotype may involve the control of haem, leading to controlled levels of HO‐1 and milder proinflammatory responses during acute malaria.

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Related in: MedlinePlus

Anti‐inflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010, ***P < 0·001; ****P < 0·000; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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cei12936-fig-0007: Anti‐inflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010, ***P < 0·001; ****P < 0·000; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]

Mentions: Plasma concentrations of four anti‐inflammatory cytokines (IL‐4, IL‐7, IL‐13 and IL‐10) were also quantified in the two groups at convalescence and during malaria infection. Levels observed during malaria infection were compared with levels at convalescence. Similar patterns of anti‐inflammatory response were observed within each genotype. For IL‐4 and IL‐7, plasma concentrations increased significantly during malaria infection within both genotypical groups (HbAA IL‐4 P = 0·010, IL‐7 P = 0·010; HbAS IL‐4 P < 0·001, IL‐7 P = 0·004) (Fig. 7a, b). Levels of IL‐13 also increased significantly during malaria infection in both genotypical groups (HbAS, P = 0·030 and HbAA, P = 0·050); however, the increase was at borderline significance in the HbAA group. Plasma concentrations of IL‐10 did not differ significantly during malaria infection compared with levels at convalescence in both haemoglobin genotypes (HbAA, P > 0·900; HbAS, P > 0·900) (Fig. 7d).


Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection
Anti‐inflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010, ***P < 0·001; ****P < 0·000; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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getmorefigures.php?uid=PMC5383446&req=5

cei12936-fig-0007: Anti‐inflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010, ***P < 0·001; ****P < 0·000; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
Mentions: Plasma concentrations of four anti‐inflammatory cytokines (IL‐4, IL‐7, IL‐13 and IL‐10) were also quantified in the two groups at convalescence and during malaria infection. Levels observed during malaria infection were compared with levels at convalescence. Similar patterns of anti‐inflammatory response were observed within each genotype. For IL‐4 and IL‐7, plasma concentrations increased significantly during malaria infection within both genotypical groups (HbAA IL‐4 P = 0·010, IL‐7 P = 0·010; HbAS IL‐4 P < 0·001, IL‐7 P = 0·004) (Fig. 7a, b). Levels of IL‐13 also increased significantly during malaria infection in both genotypical groups (HbAS, P = 0·030 and HbAA, P = 0·050); however, the increase was at borderline significance in the HbAA group. Plasma concentrations of IL‐10 did not differ significantly during malaria infection compared with levels at convalescence in both haemoglobin genotypes (HbAA, P > 0·900; HbAS, P > 0·900) (Fig. 7d).

View Article: PubMed Central - PubMed

ABSTRACT

The controlled induction of haemoxygenase&#8208;1 (HO&#8208;1), an enzyme that catabolizes haem, has been shown to reduce haem, preventing pathologies associated with haem toxicity. The hemoglobin genotype HbAS confers reduced susceptibility to severe complications of malaria by a mechanism that is not well understood. Using a longitudinal approach, we investigated the effect of baseline concentrations of HO&#8208;1 on the accumulation of haem during acute Plasmodium falciparum malaria in HbAS and HbAA genotypes. Plasma concentrations of haem, HO&#8208;1 and cytokines were quantified in venous blood obtained from children (9 months&ndash;5 years of age) during malaria infection, and at convalescence (baseline levels). Parasitaemia was determined during malaria infection. In patients with the HbAA genotype, there was a significant elevation in the plasma concentration of haem (P&thinsp;=&thinsp;0.002), and a consequent increased induction of HO&#8208;1 (P&thinsp;&lt;&thinsp;0.001) during falciparum malaria compared with levels at convalescence. Contrary to HbAA, plasma concentration of haem did not change in the HbAS genotypical group (P&thinsp;=&thinsp;0&middot;110), and the induction of HO&#8208;1 was reduced during malaria compared with levels at convalescence (P&thinsp;=&thinsp;0&middot;006). Higher plasma levels of haem were observed in HbAS compared with HbAA at convalescence (P&thinsp;=&thinsp;0&middot;010), but this difference did not affect the levels of HO&#8208;1 within each genotype (P&thinsp;=&thinsp;0&middot;450). Relatively milder proinflammatory responses were observed in HbAS children during malaria infection compared to HbAA children. Our findings suggest that a mechanism of reduced susceptibility to severe malaria pathologies by the HbAS genotype may involve the control of haem, leading to controlled levels of HO&#8208;1 and milder proinflammatory responses during acute malaria.

No MeSH data available.


Related in: MedlinePlus